Gonadal steroids are major neuroregulators and presumably underlie gender-related differences (sexual dimorphisms) in brain structure and function. We have studied reproductive endocrine-related mood disorders as well as developed endocrine models for these disorders in order to characterize the role of gonadal steroids in affective disturbance. Our major recent findings are as follows: 1) Preliminary demonstration that continuous administration of combined estradiol and progesterone eliminates premenstrual syndrome in the context of ovarian suppressive therapy (i.e., it is the change in hormones that precipitates depression in this subgroup); 2) Confirmation that approximately 50% of women with PMS will not show a therapeutic response to ovarian suppression; 3) Demonstration that under induced hypogonadal conditions, men have an exaggerated cortisol response to both CRH and exercise compared with women (thus contradicting assumptions that observed dimorphisms were consequent to activational effects of gonadal steroids); 4) Demonstration that one can distinguish PMS patients with and without past history of depression on the basis of the approximate entropy (ApEN) of their daily ratings (i.e., those PMS patients with a history of depression have low ApEN values indicating highly ordered data); 5) Identification of three distinct statistical axes that, employing mood ratings, distinguish patients with recurrent brief depression, PMS with history of depression, PMS without history of depression, and normal controls: standard deviation, ApEN, ratio of incremental standard deviation to baseline standard deviation (a measure of brief and staccato dynamics), and kurtosis (a measure of peakedness). These observations are of both theoretical and practical import. They more precisely define the physiologic trigger of PMS, help identify the physiological modulators of the HPA axis (which is disturbed in PMS), and suggest a mathematical means of phenotyping that may facilitate prediction of treatment response. Additionally, the data with continuous hormone administration may not only inform our understanding of the relevant hormonal stimuli that precipitate PMS, but as well may suggest a new therapeutic strategy for the millions of women who suffer from this disorder.